Three Part Question

In [adults with shock and where septic myocardial depression is considered to be a significant causative factor] does [levosimendan] [improve outcome]?

Clinical Scenario

A 50-year-old man attends the emergency department with a history of cough, shortness of breath and purulent sputum production. He is hypoxic and shocked. He requires intubation and ventilation, and his post-intubation chest X-ray is consistent with bronchopneumonia. Following appropriate fluid resuscitation, he remains hypotensive and norepinephrine is commenced. Despite rapidly escalating norepinephrine, additional fluids and corticosteroids (for their catecholamine sparing effect), he remains shocked. A bedside transthoracic echocardiogram demonstrates left ventricular dysfunction which you feel may be attributed to septic myocardial depression. You wonder whether he might benefit from the addition of levosimendan.

Search Strategy

Medline (1950 – January week 3, 2014), Embase (1980 to 2014, week 3) and the Cochrane library were searched via an Ovid interface: [Levosimendan] AND [(sepsis) OR (septic) OR (septic shock) OR (septicaemia). Limit search to English language.

Search Outcome

94 references were found using the above search strategy, of which eight were thought to be relevant to the clinical question.

Relevant Paper(s)

Author, date and country

Patient group

Study type (level of evidence)

Outcomes

Key results

Study Weaknesses

Memis et al.2012Turkey

30 patients with septic shock requiring more CVS support than dopamine 10μg/kg/min. Patients randomized to receive either 24 hours of dobutamine (10μg/kg/min) or levosimendan (0.1μg/kg/min).

Small numbers.
Single centre. Randomization process unclear.
Un-blinded. In 13 of the patients septic shock followed either a head injury or intracerebral bleed.
Dopamine not first line choice in UK for sepsis.
Unclear what rescue therapies (if any) used.

Cardiovascular markers.

Both significantly improved SBP, DBP and MAP.

Hospital mortality.

Non-significant trend to improved mortality (13% vs. 33%; p=0.104).

Morelli et al.2010France

40 patients with septic shock who, after adequate fluid resuscitation, still required noradrenaline to maintain their MAP. Randomized to receive either levosimendan (0.2μg/kg/min) or dobutamine (5μg/kg/min).

RCT

Sublingual, microvascular blood flow.

Significant improvement in all indices of microvascular blood flow.

Small numbers.
Single centre.
Unclear randomization process.
Dose of dobutamine may not have been adequate (discussed – they did not want a direct comparison just an active comparator).

This was a pilot study. Physiological endpoints were assessed rather than clinical outcomes.

MPAP

Decreased from 29 +/-3 to 25 +/-3 mmHg, p=0.004.

PVRI

Decreased from 290 +/-77 to 214 +/-50 dynes/sec/cm5/m2, p=0.001.

RVEF

Increased from 45 +/-10 to 59 +/-10 %, p=0.002.

SvO2

Increased from 63 +/-8% to 70 +/-8%, p<0.01.

Right ventricular systolic overload

Reduced as shown by decreased MPAP, PVRI, and increased CI, SVI, and RVEF

SVI

Increased from 41 +/-11 to 45 +/-10 ml/m2, p=0.006.

Morelli et al.2005Italy

30 patients with septic shock, initially with a normal EF, who after 48 hours of treatment with fluids, noradrenaline and dobutamine developed myocardial depression (EF<45%). Randomized to receive either 24 hours of levosimendan (0.2μg/kg/min) or dobutamine (5μg/kg/min).

RCT

Mortality.

Non-significant improvement in ICU, hospital and 28-day mortality.

Single centre.
Small numbers.
Unclear randomization. Not intention to treat.
Dose of dobutamine may not have been adequate.

Comment(s)

The hypotension associated with septic shock is predominantly due to a vasodilatory state secondary to toxins. In this circumstance, a vasopressor such as norepinephrine is the most appropriate agent to improve blood pressure and systemic perfusion. In addition, end organ perfusion may be compromised by new left ventricular dysfunction. This occurs in up to half of patients with septic shock and is associated with a higher mortality (Rudiger and Singer, 2007). There are several factors thought to play a role in sepsis induced myocardial depression, and one of these is thought to be an alteration in calcium homeostasis within the cardiac myocyte secondary to circulating cytokines (Morelli, 2005). Levosimendan is an inodilator which works predominantly by enhancing myocyte sensitivity to calcium, thereby increasing the force of contraction and improving cardiac output. This would theoretically reduce some of the deleterious effects of altered calcium homeostasis displayed in sepsis induced myocardial depression. Other beneficial effects of levosimendan include relaxation of vascular smooth muscle which could lead to improvements in blood flow to areas that usually become hypoperfused such as the gut (Memis, 2012; Morelli, 2005) and ameliorating the inflammatory response. Levosimendan is a more logical choice of inotrope in septic myocardial depression compared with dobutamine, which is generally regarded as the agent of choice (usually in conjunction with vasopressors). Despite these theoretical advantages of levosimendan, this does not appear to translate into consistent evidence of an improved outcome. There does seem to be a trend in improved cardiac parameters and possibly mortality but the current data are limited by small numbers, a lack of randomised controlled trials, varying definitions of septic shock and inconsistency with dosing regimens of both levosimendan and the comparator agent. A current randomised controlled trial will hopefully help determine the role of levosimendan in septic shock. An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) has recently started recruiting patients in the UK (http://www.controlled-trials.com/ISRCTN12776039/ accessed 21 February 2014). The primary outcome being evaluated is mean Sequential Organ Failure Assessment score, and secondary outcomes include cardiac output.

Clinical Bottom Line

There are theoretical advantages to the use of levosimendan in sepsis induced myocardial depression, and evidence supports the fact that it can improve cardiovascular parameters. However, the current evidence does not demonstrate improved survival. Dobutamine in conjunction with a vasopressor is therefore likely to remain the agent of choice in the treatment of sepsis induced myocardial depression. The LeoPARDS study will help define the efficacy of levosimendan in septic shock.